The unifying theme of this proposal is to study the underlying biochemical causes of concomitants of aging by use of model cell and tissue systems in various stages of growth, development or differentiation. Processes studied are cast into 3 separate but inter-related projects. The first develops previous studies on membrane and extracellular matrix components produced by fibroblasts and smooth muscle cells. We shall examine the insoluble matrix proteins and effects of ascorbic acid and of procollagen peptides on their biosynthesis. Synthesis of specific membrane glycoproteins will be studied using techniques to distinguish dolichol-dependent glycoprotein and cholesterol syntheses; a possible function of endogenous cholesterol in glycoprotein synthesis will be sought. The second project will examine the uptake, processing and metabolism of specific small molecules usually supplied in tissue culture media, and also endocytic processes relative to internalization into lysosomes. Using fibroblasts, smooth muscle cells, myoblasts and 3T3 cells, we shall study transport, internal transformation and participation in metabolic processes of creatine, carnitine and, in some regards, of molecular oxygen. Coordinately we shall examine relevant enzymes of creatine metabolism, fatty acid metabolism, and hydroxylation. This project will deal also with the synthesis, processing, export and re-uptake of lysosomal enzymes and coordinate effects of dolichol-dependent glycoprotein synthesis in various cells. The third project is concerned with metabolism of cells in various phases of growth and differentiation with regard to provision and action of peptide growth factors and hormones, and occurrence and development of their receptors. Isolation, characterization and internalization of epidermal growth factor will be studied, and effects on morphology and metabolism determined. Effects of growth factors on opiate receptors in neuroblastoma and hybrid cells and on aminergic receptors in other cells will be examined. Adrenergic and aminergic receptors will be studied in iris of aging rabbits and rats, and in brain stem of aging normotensive and genetically hypertensive rats. Always special consideration will be stage of cell development, differentiation, age of culture, or age of animal.